title: Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study.
abstract: BACKGROUND
  New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials.
  
  
  METHODS
  In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug.
  
  
  RESULTS
  70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none).
  
  
  CONCLUSIONS
  On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: ahmad.awada@bordet.be.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Guy H M
authors.initials: GH
authors.lastname: Jerusalem
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.forename: Manon T
authors.initials: MT
authors.lastname: Huizing
authors.forename: Aminder
authors.initials: A
authors.lastname: Mehdi
authors.forename: Sue M
authors.initials: SM
authors.lastname: O'Reilly
authors.forename: John T
authors.initials: JT
authors.lastname: Hamm
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barrett-Lee
authors.forename: Veronique
authors.initials: V
authors.lastname: Cocquyt
authors.forename: Kostandinos
authors.initials: K
authors.lastname: Sideras
authors.forename: David E
authors.initials: DE
authors.lastname: Young
authors.forename: Carol
authors.initials: C
authors.lastname: Zhao
authors.forename: Yen Lin
authors.initials: YL
authors.lastname: Chia
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D057194:Intention to Treat Analysis; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014481:United States
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D059004:Topoisomerase I Inhibitors; D011092:Polyethylene Glycols; D000077146:Irinotecan; C581703:etirinotecan pegol; D002166:Camptothecin